The cancer journal
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Phase II oncologic clinical trials for agents that are mainly growth inhibitory and benefit only a selected patient population are challenging. The randomized discontinuation trial design is one approach by which this can be accomplished. ⋯ The primary end point is the fraction of patients who remain progression free after an additional postrandomization period or the time to progression after randomization. By enriching for a possible sensitive population and then testing whether this was due to the agent or selection of an indolent disease group, the randomized discontinuation trial design efficiently assesses the putative growth inhibitory properties of an investigational agent and furthermore minimizes the number of patients exposed to placebo.
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The emergence of many newer, molecularly targeted anticancer drugs requires that we rethink the way that we conduct phase II trials in oncology. In particular, we can no longer afford to advance drugs (or combinations) to phase III trials with a high risk of failure to improve on outcomes. ⋯ We use the example of advanced nonsmall cell lung cancer to demonstrate how randomized phase II trials have already made an impact in oncology, whereas single-arm phase II trials have led to negative phase III trials in the same disease. Finally, we make the case that randomized phase II trials are feasible, as long as reasonable statistical standards are applied.
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Since 1992, the Food and Drug Administration has allowed for accelerated approval of cancer drugs in cases where a statistically significant and clinically meaningful improvement in survival or side effect over alternative therapies is clearly demonstrated in controlled randomized trials. To this effect, endpoints other than overall survival (OS) are accepted as surrogate markers for survival. A lack of consensus exists regarding the validity of progression-free survival (PFS) as a true measure of outcome due to treatment. ⋯ The magnitude of the improvement in PFS is the magnitude of the improvement in OS. PFS is simply a measure of a drug's effect on tumor growth while it is administered and is not a surrogate for OS. Although PFS should not replace OS in regulatory approval consideration should be given to studies that treat beyond current definitions of progressive disease as a strategy to augment OS.
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For most clinical oncologists trained before the 1990s, a 20% or greater response rate is the convention for a drug to be considered active in phase II studies. However, this no longer holds true with several targeted therapies repeatedly achieving the regulatory criteria of progression-free and overall survival benefit with considerably lower objective response rates but a sizeable proportion of patients having stable disease. Considerable skepticism persists as to the value of stable disease as a valid outcome in early clinical trials of new agents. ⋯ Continued uncertainty of the value of stable disease is based on the lack of precision in defining this as a meaningful outcome. With the term stable disease encompassing a broad range from <20% enlargement to <30% reduction using standard response criteria response evaluation criteria in solid tumors, what one refers to as stable disease is open to diverse interpretation. The evidence that stable disease is a valid end point in many recent clinical trials is therefore discussed in this review and along with contemporary methods that bring some accuracy to the interpretation of stable disease within the context of clinical trial results.
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Phase II clinical trials have long been used to screen new cancer therapeutics for antitumor activity ("efficacy") worthy of further evaluation. Traditionally, the primary end point used in these screening trials has been objective response rate (RR), with the desired rate being arbitrarily set by the researchers before initiation of the trial. For cytotoxic agents, especially in common tumor types, response has been a reasonably robust and validated surrogate of benefit. ⋯ Researchers have postulated that these novel agents, as a class, may not induce significant regression of tumors, and that the use of RR as an end point for phase II studies will result in false negative results, and point out that not all available data is used in making the decision. Others have pointed out that even novel agents have proven unsuccessful in pivotal trials if objective responses are not demonstrated in early clinical trials. We review here the historical and current information regarding objective tumor response.